CK-7 negative primary lung adenocarcinoma

Abstract Cytokeratin (CK) 7 is normally expressed in the vast majority of lung adenocarcinoma (ADC). However, on rare occasions, as reported in this paper, CK7 negativity can challenge the diagnosis of pulmonary ADC. Hence, the need to use a combination of ‘immunomarkers’ such as thyroid transcription factor 1, Napsin A, p40, p63 and CK20.


INTRODUCTION
Lung cancer, the most common cause of cancer-related death, is now characterized further by immunohistochemistry that helps identified targeted therapies. This helps for optimal patient selection for specific therapies based on driver mutations. Nonsmall cell lung cancer (NSCLC) not otherwise specified is now classified into adenocarcinoma (ADC), squamous or large cell carcinoma [1,2]. The latter is the default nomination when all 'immunomarkers' are negative [1]. Squamous carcinoma responds to tumor proteins p40, p63 and cytokeratin (CK) 5/6 [1,3,4]. Commonly used markers for ADC are thyroid transcription factor 1 (TTF-1), Napsin A, CK7 and CK AE1/3 [1,3,4]. Although the sensitivity and specificity of these markers are variable, CK7 positivity strongly indicates ADC [5,6]. We are hereby reporting a very rare CK7-negative lung ADC and discussing its implications.

CASE PRESENTATION
A 60-year-old female with a past medical history of Barrett's esophagus was admitted with dysphagia to solid foods. The patient reported unintentional weight loss and needed excessive chewing of food and f luids to wash it down. A total of 1 month before admission, the patient's esophagogastroduodenoscopy showed an 8 cm, near-obstructing, circumferential, ulcerated friable mass extending from the middle third to the lower third of the esophagus. An esophageal biopsy was done, and the pathology report shows Barrett's esophagus without dysplasia. The computer tomography chest/abdomen/pelvis findings showed a large subcarinal mediastinal mass, likely representing a primary esophageal pathology as described previously. Other findings included right hilar adenopathy and an irregular spiculated lesion in the right lower lobe, which could represent a primary lung malignancy. Biopsy from bronchoscopy and bronchoalveolar lavage revealed a moderately differentiated ADC.

PATHOLOGY
Pathology evaluation from the right middle lobe biopsy showed few clusters of malignant cells, consistent with ADC (Fig. 1). Immunohistochemical staining showed tumor cells were positive for AE1/3, Napsin A and TTF1 (Fig. 2), with ∼60% Ki-67 positivity. Tumor cells were also negative for CK7 (Fig. 3), p40, p63, CK20 and CK5/6. The overall tumor morphology features and immunoprofile favored moderately differentiated ADC of the lung. However, other primary sites could not be ruled out.
Correct identification and classification of primary or metastatic lung ADC can be achieved by coupling CK7 with other markers such as TTF1 and Napsin A [9]. Current management of primary ADCs includes surgery, chemotherapy, radiation therapy and targeted therapy but none is related to CK7. Hence, its status will not interfere with the treatment approaches. Also, prognostic factors are mainly the depth of tumor invasion and metastasis status, not CK7 status.
There are not enough case reports of CK7 negativity to warrant a reclassification of NSCLCs.

CONCLUSION
Proper identification of primary ADC can be done using Napsin A+, TTF1 and/or CK7. Though CK7 is normally expressed in lung tissue, in rare cases, CK7 is negative in primary lung ADC. Management and prognosis of ADC should not be affected by CK7 status.